Longitudinal evaluation of asymptomatic Leishmania infection in HIV-infected individuals in North-West Ethiopia: A pilot study

Johan van Griensven, Saskia van Henten, Bewketu Mengesha, Mekibib Kassa, Emebet Adem, Mengistu Endris Seid, Saïd Abdellati, Wondimu Asefa, Tesfa Simegn, Degnachew Debasu, Tadfe Bogale, Yonas Gedamu, Dorien Van Den Bossche, Wim Adriaensen, Gert Van der Auwera, Lieselotte Cnops, Florian Vogt, Ermias Diro, Johan van Griensven, Saskia van Henten, Bewketu Mengesha, Mekibib Kassa, Emebet Adem, Mengistu Endris Seid, Saïd Abdellati, Wondimu Asefa, Tesfa Simegn, Degnachew Debasu, Tadfe Bogale, Yonas Gedamu, Dorien Van Den Bossche, Wim Adriaensen, Gert Van der Auwera, Lieselotte Cnops, Florian Vogt, Ermias Diro

Abstract

Background: In endemic regions, asymptomatic Leishmania infection is common. In HIV patients, detection of asymptomatic Leishmania infection could potentially identify those at risk of visceral leishmaniasis (VL). However, data on the prevalence, incidence, and determinants of asymptomatic infection, and the risk of VL are lacking.

Methods: We conducted a cross-sectional survey at a single ART centre, followed by a prospective cohort study amongst HIV-infected adults in HIV care in a district hospital in a VL-endemic area in North-West Ethiopia (9/2015-8/2016). Asymptomatic Leishmania infection was detected using the direct agglutination test (DAT), rK39-rapid diagnostic test (RDT)), PCR on peripheral blood and the KAtex urine antigen test, and defined as positivity on any Leishmania marker. All individuals were followed longitudinally (irrespective of the Leishmania test results). Risk factors for asymptomatic Leishmania infection were determined using logistic regression.

Results: A total of 534 HIV-infected individuals enrolled in HIV care were included in the study. After excluding 13 patients with a history of VL and an 10 patients with incomplete baseline Leishmania tests, 511 were included in analysis. The median age was 38 years (interquartile range (IQR) 30-45), 62.6% were male. The median follow-up time was 12 months (IQR 9-12). No deaths were reported during the study period. Most (95.5%) were on antiretroviral treatment at enrolment, for a median of 52 months (IQR 27-79). The median CD4 count at enrolment was 377 cells/mm3 (IQR 250-518). The baseline prevalence of Leishmania infection was 12.8% in males and 4.2% in females. Overall, 7.4% tested positive for rK39, 4.3% for DAT, 0.2% for PCR and 0.2% for KAtex. Independent risk factors for a prevalent infection were male sex (odds ratio (OR) 3.2; 95% confidence intervals (CI) 14-7.0) and concurrent malaria infection (OR 6.1; 95% CI 1.9-18.9). Amongst the 49 prevalent (baseline) infections with further follow-up, the cumulative incidence of losing the Leishmania markers by one year was 40.1%. There were 36 incident infections during the course of the study, with a cumulative one-year risk of 9.5%. Only one case of VL was detected during follow-up.

Conclusions: We found a high prevalence of asymptomatic Leishmania infection, persisting in most cases. The incidence was more modest and overt VL was rare. Larger and longer studies with more complete follow-up may help to decide whether a test and treat strategy would be justified in this context.

Trial registration: ClinicalTrials.gov NCT02839603.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Type of positive Leishmania markers…
Fig 1. Type of positive Leishmania markers at the time of recruitment in the study (prevalence).
DAT: direct agglutination test; PCR: polymerase chain reaction.

References

    1. van Griensven J, Diro E. Visceral leishmaniasis. Infect Dis Clin North Am. 2012;26(2):309–22. Epub 2012/05/29. 10.1016/j.idc.2012.03.005 .
    1. Alvar J, Aparicio P, Aseffa A, Den Boer M, Canavate C, Dedet JP, et al. The relationship between leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev. 2008;21(2):334–59. Epub 2008/04/11. 10.1128/CMR.00061-07 .
    1. Molina R, Canavate C, Cercenado E, Laguna F, Lopez-Velez R, Alvar J. Indirect xenodiagnosis of visceral leishmaniasis in 10 HIV-infected patients using colonized Phlebotomus perniciosus. AIDS. 1994;8(2):277–9. Epub 1994/02/01. 10.1097/00002030-199402000-00024 .
    1. Molina R, Gradoni L, Alvar J. HIV and the transmission of Leishmania. Ann Trop Med Parasitol. 2003;97 Suppl 1:29–45. Epub 2003/12/18. 10.1179/000349803225002516 .
    1. Ferreira GR, Castelo Branco Ribeiro JC, Meneses Filho A, de Jesus Cardoso Farias Pereira T, Parente DM, Pereira HF, et al. Human Competence to Transmit Leishmania infantum to Lutzomyia longipalpis and the Influence of Human Immunodeficiency Virus Infection. Am J Trop Med Hyg. 2018;98(1):126–33. Epub 2017/11/17. 10.4269/ajtmh.16-0883 .
    1. Hurissa Z, Gebre-Silassie S, Hailu W, Tefera T, Lalloo DG, Cuevas LE, et al. Clinical characteristics and treatment outcome of patients with visceral leishmaniasis and HIV co-infection in northwest Ethiopia. Trop Med Int Health. 2010;15(7):848–55. Epub 2010/05/22. 10.1111/j.1365-3156.2010.02550.x .
    1. Ritmeijer K, ter Horst R, Chane S, Aderie EM, Piening T, Collin SM, et al. Limited effectiveness of high-dose liposomal amphotericin B (AmBisome) for treatment of visceral leishmaniasis in an Ethiopian population with high HIV prevalence. Clin Infect Dis. 2011;53(12):e152–8. Epub 2011/10/22. 10.1093/cid/cir674 .
    1. Word Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach, 2006 Revision2006.
    1. WHO. Control of the leishmaniasis. Report of a meeting of the WHO Expert Committee on the Control of Leishmaniases, Geneva, 22–26 March 2010. WHO technical report series 9492010.
    1. Michel G, Pomares C, Ferrua B, Marty P. Importance of worldwide asymptomatic carriers of Leishmania infantum (L. chagasi) in human. Acta Trop. 2011;119(2–3):69–75. Epub 2011/06/18. 10.1016/j.actatropica.2011.05.012 .
    1. Hailu A, Gramiccia M, Kager PA. Visceral leishmaniasis in Aba-Roba, south-western Ethiopia: prevalence and incidence of active and subclinical infections. Ann Trop Med Parasitol. 2009;103(8):659–70. Epub 2009/12/25. 10.1179/000349809X12554106963555 .
    1. van Griensven J, Diro E, Lopez-Velez R, Ritmeijer K, Boelaert M, Zijlstra EE, et al. A screen-and-treat strategy targeting visceral leishmaniasis in HIV-infected individuals in endemic East African countries: the way forward? PLoS Negl Trop Dis. 2014;8(8):e3011 Epub 2014/08/08. 10.1371/journal.pntd.0003011 .
    1. Diro E, Lynen L, Ritmeijer K, Boelaert M, Hailu A, van Griensven J. Visceral Leishmaniasis and HIV coinfection in East Africa. PLoS Negl Trop Dis. 2014;8(6):e2869 10.1371/journal.pntd.0002869 .
    1. WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection Recommendations for a public health approach—Second edition2016.
    1. Ministry of Health FRoE. National guidelines for comprehensive HIV prevention, treatment and control2014.
    1. Gadisa E, Tsegaw T, Abera A, Elnaiem DE, den Boer M, Aseffa A, et al. Eco-epidemiology of visceral leishmaniasis in Ethiopia. Parasit Vectors. 2015;8:381 Epub 2015/07/19. 10.1186/s13071-015-0987-y .
    1. Abbasi I, Aramin S, Hailu A, Shiferaw W, Kassahun A, Belay S, et al. Evaluation of PCR procedures for detecting and quantifying Leishmania donovani DNA in large numbers of dried human blood samples from a visceral leishmaniasis focus in Northern Ethiopia. BMC Infect Dis. 2013;13:153 Epub 2013/03/28. 10.1186/1471-2334-13-153 .
    1. Vogt F, Mengesha B, Asmamaw H, Mekonnen T, Fikre H, Takele Y, et al. Antigen Detection in Urine for Noninvasive Diagnosis and Treatment Monitoring of Visceral Leishmaniasis in Human Immunodeficiency Virus Coinfected Patients: An Exploratory Analysis from Ethiopia. Am J Trop Med Hyg. 2018;99(4):957–66. Epub 2018/08/08. 10.4269/ajtmh.18-0042 .
    1. Boelaert M, Verdonck K, Menten J, Sunyoto T, van Griensven J, Chappuis F, et al. Rapid tests for the diagnosis of visceral leishmaniasis in patients with suspected disease. Cochrane Database Syst Rev. 2014;(6):CD009135 10.1002/14651858.CD009135.pub2 .
    1. Hasker E, Kansal S, Malaviya P, Gidwani K, Picado A, Singh RP, et al. Latent infection with Leishmania donovani in highly endemic villages in Bihar, India. PLoS Negl Trop Dis. 2013;7(2):e2053 Epub 2013/03/06. 10.1371/journal.pntd.0002053 .
    1. Singh OP, Hasker E, Sacks D, Boelaert M, Sundar S. Asymptomatic Leishmania infection: a new challenge for Leishmania control. Clin Infect Dis. 2014;58(10):1424–9. Epub 2014/03/04. 10.1093/cid/ciu102 .
    1. Custodio E, Gadisa E, Sordo L, Cruz I, Moreno J, Nieto J, et al. Factors associated with Leishmania asymptomatic infection: results from a cross-sectional survey in highland northern Ethiopia. PLoS Negl Trop Dis. 2012;6(9):e1813 Epub 2012/10/03. 10.1371/journal.pntd.0001813 .
    1. Gadisa E, Custodio E, Canavate C, Sordo L, Abebe Z, Nieto J, et al. Usefulness of the rK39-immunochromatographic test, direct agglutination test, and leishmanin skin test for detecting asymptomatic Leishmania infection in children in a new visceral leishmaniasis focus in Amhara State, Ethiopia. Am J Trop Med Hyg. 2012;86(5):792–8. Epub 2012/05/05. 10.4269/ajtmh.2012.11-0196 .
    1. Sordo L, Gadisa E, Custodio E, Cruz I, Simon F, Abraham Z, et al. Low prevalence of Leishmania infection in post-epidemic areas of Libo Kemkem, Ethiopia. Am J Trop Med Hyg. 2012;86(6):955–8. Epub 2012/06/06. 10.4269/ajtmh.2012.11-0436 .
    1. Low A, Gavriilidis G, Larke N, MR BL, Drouin O, Stover J, et al. Incidence of Opportunistic Infections and the Impact of Antiretroviral Therapy Among HIV-Infected Adults in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis. Clin Infect Dis. 2016;62(12):1595–603. Epub 2016/03/10. 10.1093/cid/ciw125 .
    1. Ghosh K, Javeri KN, Mohanty D, Parmar BD, Surati RR, Joshi SH. False-positive serological tests in acute malaria. Br J Biomed Sci. 2001;58(1):20–3. Epub 2001/04/04. .
    1. Saha P, Ganguly S, Chatterjee M, Das SB, Kundu PK, Guha SK, et al. Asymptomatic leishmaniasis in kala-azar endemic areas of Malda district, West Bengal, India. PLoS Negl Trop Dis. 2017;11(2):e0005391 10.1371/journal.pntd.0005391 .
    1. Topno RK, Das VN, Ranjan A, Pandey K, Singh D, Kumar N, et al. Asymptomatic infection with visceral leishmaniasis in a disease-endemic area in bihar, India. Am J Trop Med Hyg. 2010;83(3):502–6. 10.4269/ajtmh.2010.09-0345 .
    1. Kirstein OD, Skrip L, Abassi I, Iungman T, Horwitz BZ, Gebresilassie A, et al. A fine scale eco-epidemiological study on endemic visceral leishmaniasis in north ethiopian villages. Acta Trop. 2018;183:64–77. 10.1016/j.actatropica.2018.04.005 .
    1. Zijlstra EE, el-Hassan AM, Ismael A, Ghalib HW. Endemic kala-azar in eastern Sudan: a longitudinal study on the incidence of clinical and subclinical infection and post-kala-azar dermal leishmaniasis. Am J Trop Med Hyg. 1994;51(6):826–36. Epub 1994/12/01. 10.4269/ajtmh.1994.51.826 .
    1. Ostyn B, Gidwani K, Khanal B, Picado A, Chappuis F, Singh SP, et al. Incidence of symptomatic and asymptomatic Leishmania donovani infections in high-endemic foci in India and Nepal: a prospective study. PLoS Negl Trop Dis. 2011;5(10):e1284 Epub 2011/10/13. 10.1371/journal.pntd.0001284 .
    1. Diro E, van Griensven J, Mohammed R, Colebunders R, Asefa M, Hailu A, et al. Atypical manifestations of visceral leishmaniasis in patients with HIV in north Ethiopia: a gap in guidelines for the management of opportunistic infections in resource poor settings. Lancet Infect Dis. 2015;15(1):122–9. 10.1016/S1473-3099(14)70833-3 .
    1. Vallur AC, Tutterrow YL, Mohamath R, Pattabhi S, Hailu A, Abdoun AO, et al. Development and comparative evaluation of two antigen detection tests for Visceral Leishmaniasis. BMC Infect Dis. 2015;15:384 10.1186/s12879-015-1125-3 .

Source: PubMed

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